Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH2:23]([O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1[CH:30]=O)[CH:24]([CH3:26])[CH3:25].[O-]CC.[Na+]>C(O)C>[CH2:23]([O:27][C:28]1[C:35]([O:36][CH3:37])=[CH:34][CH:33]=[CH:32][C:29]=1/[CH:30]=[CH:1]/[C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Reactant: COc1cccc(C=O)c1OCC(C)C
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC(C)C
Yield: 33.8 %

Procedure:
The title compound was synthesized by condensation of Intermediate 15 (350 mg, 1.071 mmol) with 2-isobutoxy-3-methoxybenzaldehyde (312 mg, 1.516 mmol) in the presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure of Example 24 to give 187 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.90-0.99 (m, 6H), 1.80-1.86 (m, 1H), 3.58-3.65 (m, 2H), 3.77 (s, 3H), 6.85-6.93 (m, 2H), 6.99-7.06 (m, 2H), 7.40-7.50 (m, 5H), 7.96-8.02 (m, 1H), 8.09-8.14 (m, 1H); ESI-MS (m/z) 517.18 (M+H)+.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH:12]=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[CH2:12][OH:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1ccc(CO)cc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a cooled solution of 3-[(tert-Butyldimethylsilyl)oxy]-4-methoxybenzaldehyde 13 (17.5 g, 65.7 mmol) in methanol (100 mL) under nitrogen, sodium borohydride (2.98 g, 78.8 mmol) was added and stirred at room temperature for 30 min. After the reaction was complete as indicated by TLC (chloroform on silica gel plate), ice was added to the reaction mixture and extracted with ethyl acetate. The organic layer was separated, washed with water and dried. Removal of solvent in vacuo yielded on yellow oil 14 (73.5%). 1H NMR: δ 0.18 (s, 6H, 2×CH3), 1.00 (s, 9H, 3×CH3), 1.90 (br s, 1H, OH), 3.82 (s, 3H, OCH3), 4.56 (s, 2H, CH2OH), 6.94 (br s, 3H, Ar—H). Anal. Calcd for C14H24O3Si: C, 62.64, H, 9.01. Found: C, 62.59, H, 9.03.
Reaction SMILES: [C:1]([Cl:11])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH:12]([NH:15][C:16](=[O:24])[CH2:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:14])[CH3:13]>C(Cl)Cl>[ClH:11].[CH:12]([NH:15][C:16](=[O:24])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:1](=[O:10])[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)([CH3:14])[CH3:13]
Reactant: CC(C)NC(=O)CN1CCNCC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCN(CC(=O)NC(C)C)CC2)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4.6 g of anisic acid chloride in 20 ml of methylene chloride is added dropwise to 5 g of piperazinoacetic acid isopropylamide in 20 ml of methylene chloride at 0° C. The mixture is then stirred at room temperature for 4 hours and subsequently concentrated. The residue is recrystallised from isopropanol.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][NH2:9])=O.[CH2:10]([N:17]=[C:18]=[S:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:10]([N:17]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[N:8][N:9]=[C:18]1[S:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: S=C=NCc1ccccc1
Reactant: NNC(=O)c1ccco1
Reactant: BrCc1ccccc1
Product: c1ccc(CSc2nnc(-c3ccco3)n2Cc2ccccc2)cc1

Procedure:
This compound was synthesized using the same methodology as described in Example 1 above, using 2-furancarboxylic acid hydrazide, benzyl isothiocyanate and benzyl bromide as the starting materials. (M+H)+−348.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:12]=[CH:13]/[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:9]=2)[CH2:4]1.C(N(CC)CC)C.Cl[C:29]1[C:30]2[C:37]([CH3:38])=[CH:36][S:35][C:31]=2[N:32]=[CH:33][N:34]=1>C(O)C>[CH3:20][C:17]1[CH:16]=[CH:15][C:14](/[CH:13]=[CH:12]/[C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH2:4][CH:3]([NH:2][C:29]2[C:30]4[C:37]([CH3:38])=[CH:36][S:35][C:31]=4[N:32]=[CH:33][N:34]=2)[CH2:11]3)=[CH:19][CH:18]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: Cc1ccc(/C=C/c2ccc3c(c2)CC(N)C3)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1ccc(/C=C/c2ccc3c(c2)CC(Nc2ncnc4scc(C)c24)C3)cc1
Yield: 58.3 %

Procedure:
Using 2-amino-5-[(E)-2-(4-methylphenyl)ethenyl]indan hydrochloride (16 mg, 0.06 mmol), ethanol (0.6 ml), triethylamine (50 μl, 0.36 mmol), and 4-chloro-5-methylthieno[2,3-d]pyrimidine (11 mg, 0.060 mmol), a similar procedure to b) in Production Example 208 was carried out The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=4:1) to obtain the title compound (14 mg, 0.035 mmol) having the following physical properties:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[Si](C)(C)CC[Si]2(C)C)=[N:6][CH:7]=1.[SH:17][CH2:18][CH2:19][OH:20].CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([S:17][CH2:18][CH2:19][OH:20])=[CH:3][CH:4]=1
Reactant: OCCS
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(SCCO)cn1
Temperature: 110 °C
Reaction time: 17 h
Yield: 95.7 %

Procedure:
In a 100 mL round-bottomed flask, 5-bromo-2-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)pyridine (502 mg, 1.59 mmol), 2-mercaptoethanol (124 mg, 112 μl, 1.59 mmol), xantphos (46.1 mg, 79.6 μmol) and Hunig's base (411 mg, 556 μl, 3.18 mmol) were combined with dioxane (10.0 ml) to give a light yellow solution. Pd2(dba)3 (36.4 mg, 39.8 μmol) was added and the mixture was evacuated and filled with argon. The reaction mixture was heated to 110° C. and stirred for 17 h under argon. The reaction mixture was cooled to 25° C., concentrated in vacuo and partitioned between 1M HCl and EtOAc. Separated and basified aqueous with 3M NaOH. The aqueous layer was extracted with EtOAc (3×125 mL). The organic layers were combined, washed with sat NaCl (1×25 mL), dried over Na2SO4 and concentrated in vacuo to a light yellow solid. The solid was dried under vacuum at 25° C. for 21 hrs to afford 0.259 g (96%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ: 7.94 (d, J=2.3 Hz, 1H), 7.45 (dd, J=8.7, 2.3 Hz, 1H), 6.40 (d, J=8.7 Hz, 1H), 6.03-6.20 (m, 2H), 4.77 (t, J=5.7 Hz, 1H), 3.37-3.51 (m, 2H), 2.67-2.76 (m, 2H).
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].C(Cl)Cl.[CH:8]([CH:10]1[CH2:14][S:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]1[C:21]([O:23][CH3:24])=[O:22])=[O:9].[Cl-].[NH4+]>CO>[OH:9][CH:8]([CH:10]1[CH2:14][S:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:11]1[C:21]([O:23][CH3:24])=[O:22])[CH:1]=[CH2:2]
Reactant: C=C[Mg]Cl
Reactant: COC(=O)N1C(C=O)CSC1c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: C=CC(O)C1CSC(c2ccccc2)N1C(=O)OC
Reaction time: 0.5 h
Yield: 87 %

Procedure:
To a mixture of 310 ml. (0.440 mole) of vinylmagnesium chloride (from Ventron Corp., 1.42 molar in tetrahydrofuran) and 250 ml. of methylene chloride, which had been previously prepared and kept at -74°C., a solution of 14.2 g. (0.0565 mol) of 4-formyl-3-carbomethoxy-2-phenylthiazolidine dissolved in 50 ml. of methylene chloride was added over a period of 7-10 minutes, while the temperature of the reaction was kept at -60° to -70°C. After addition, the reaction mixture was stirred for 30 minutes at the same temperature while 30 ml. of methanol were slowly added, followed by addition of 150 ml. of saturated ammonium chloride. When the addition was finished, the mixture was allowed to reach room temperature and extracted with 3 × 300 ml. of methylene chloride. The combined organic phases were washed with 2 × 200 ml. of water, dried with sodium sulfate, and evaporated to give 13.7 g. (87% yield) of crude 4-(1-hydroxyprop-2-en-1-yl)-3-carbomethoxy-2-phenylthiazolidine which was obtained as thick oil. This contains a small amount of starting material which, for future separation purposes, is convenient to convert into its corresponding alcohol. To this end, the crude product, dissolved in 100 ml. of tetrahydrofuran was slowly added to a solution of 0.9 g. (0.0503 mol) of sodium borohydride in 75 ml. of water and 75 ml. of tetrahydrofuran. After addition, the resulting yellow emulsion was stirred for 2 hours at room temperature. 55 ml. of 1N hydrochloric acid were then slowly added, the tetrahydrofuran removed in vacuo and the residue extracted with 3 × 100 ml. of ethyl acetate. The combined organic phases were washed with 100 ml. of 5% sodium bicarbonate solution and finally with 2 × 100 ml. of water. Drying with magnesium sulfate and evaporating the solvent gave 13.0 g. of the desired product, which can be used as such for the further transformations or it can be further purified by chromatography on silica gel, using benzene/ethyl acetate (1:1) as eluent. 4.1 g. (corresponding to a yield of 26% from a starting material) of very pure product was obtained as pale yellow thick oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[C:4](Cl)=[O:5].[C:8]([C:11]1[CH:30]=[CH:29][C:14]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]([C:24]([CH3:28])=[CH:25][C:26]=2[Br:27])[NH2:23])=[C:13]([CH2:31][CH2:32][CH3:33])[C:12]=1[OH:34])(=[O:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:7])[C:4]([NH:23][C:22]1[C:24]([CH3:28])=[CH:25][C:26]([Br:27])=[C:20]([O:19][CH2:18][CH2:17][CH2:16][O:15][C:14]2[CH:29]=[CH:30][C:11]([C:8](=[O:10])[CH3:9])=[C:12]([OH:34])[C:13]=2[CH2:31][CH2:32][CH3:33])[CH:21]=1)=[O:5]
Reactant: CCCc1c(OCCCOc2cc(N)c(C)cc2Br)ccc(C(C)=O)c1O
Reactant: COC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1c(OCCCOc2cc(NC(=O)C(=O)OC)c(C)cc2Br)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In the course of approximately 5 minutes a solution of 3.2 ml of chloro-oxalic acid methyl ester in 10 ml of methylene chloride is added dropwise to a solution, cooled to 0°, of 14.0 g (32 mmol) of 3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylaniline and 4.9 ml of triethylamine in 140 ml of methylene chloride and the whole is then stirred at room temperature for a further 90 minutes. The reaction mixture is poured onto ice-water and the organic phase is separated off, washed with water, dried over sodium sulphate and concentrated under reduced pressure. Crystallisation from ethyl acetate/ether/petroleum ether yields N-{3-[3-(4-acetyl-3-hydroxy-2-n-propylphenoxy)-propoxy]-4-bromo-6-methylphenyl}-oxamic acid methyl ester having a melting point of 92°-93°.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].O.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=1>C(Cl)Cl>[C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10].[NH2:13][N+:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][OH:23])[CH:17]=1
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: OCc1cccnc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: N[n+]1cccc(CO)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of O-mesitylenesulfonylhydroxylamine, ˜30-35% water, (14.5 g, 52 mmol) and CH2Cl2 (100 mL) is added to a solution of 3-pyridylcarbinol (5.0 mL, 52 mmol) and CH2Cl2 (100 mL) at 0° C. dropwise over 40 min. After 30 min at 0° C., the ice bath is removed and the solution is stirred at ambient temperature for 20 min. The volatiles are removed under reduced pressure to afford N-amino-3-hydroxymethylpyridinium mesityl sulfonate as a yellow oil. DMF (100 mL) and K2CO3 (15 g, 110 mmol) are added. The dark brown mixture is cooled in a water bath. Dimethyl acetylenedicarboxylate (6.9 mL, 56 mmol) are added dropwise over 10 min. After 15 min, the water bath is removed and the mixture is left to vigorously stir under air for 18 h. After filtering through Celite (CH2Cl2 rinse), the volatiles are removed under reduced pressure. The residue is slurried in EtOAc and the mixture is filtered through Celite (EtOAc rinse). The volatiles are removed under reduced pressure to afford a dark brown oil. Purification by flash column chromatography (2:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) affords the title compound as a light yellow solid. LC-MS m/z (M+Na+): 287.08§.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][NH:5][CH2:4][CH:3]1[NH:7][C:8]([C:10]1[C:14]([CH3:15])=[C:13](/[CH:16]=[C:17]2\[C:18](=[O:27])[NH:19][C:20]3[C:25]\2=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[NH:12][C:11]=1[CH3:28])=[O:9].CCN(C(C)C)C(C)C.[CH3:38][C:39](Cl)=[O:40]>>[C:39]([N:5]1[CH2:6][CH:2]([OH:1])[CH:3]([NH:7][C:8]([C:10]2[C:14]([CH3:15])=[C:13](/[CH:16]=[C:17]3\[C:18](=[O:27])[NH:19][C:20]4[C:25]\3=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[NH:12][C:11]=2[CH3:28])=[O:9])[CH2:4]1)(=[O:40])[CH3:38]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC1CNCC1O
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC(O)C(NC(=O)c2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(F)cc43)c2C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.3 %

Procedure:
To the solution of 5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-hydroxy-pyrrolidin-3-yl)-amide (150 mg, 0.39 mmol) and DIEA (89 mg, 0.69 mmol) was added CH3COCl (33.7 mg, 0.43 mmol) on an ice bath. The mixture was stirred at r.t. for 3 hrs. After the reaction was complete, DMF was evaporated under reduced pressure and the residue was triturated with methanol and the solid was collected by filtration, washed with ethanol and dried in vacuum to give title compound (82 mg, 57% yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6): δ=13.67 (s, 1H), 10.87 (s, 1H), 8.07-8.10 (d, 1H), 7.71-7.85 (m, 3H), 6.82-6.92 (m, 2H), 5.34-5.44 (dd, 1H), 4.13-4.18 (d, 2H), 3.67-3.81 (m, 4H), 2.38-2.40 (ds, 6H), 1.92-1.93 (d, 3H). LC/MS: 427.0 [M+H]+.
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:54]=[CH:53][C:52]([NH:55][C:56]([C:58]4[O:59][C:60]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=5)=[CH:61][N:62]=4)=[O:57])=[CH:51][CH:50]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([O:38]C)=[O:37]>>[CH3:33][CH:34]([CH3:70])[C@H:35]([N:40]1[CH2:48][C:47]2[C:42](=[CH:43][C:44]([C:49]3[CH:50]=[CH:51][C:52]([NH:55][C:56]([C:58]4[O:59][C:60]([C:63]5[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=5)=[CH:61][N:62]=4)=[O:57])=[CH:53][CH:54]=3)=[CH:45][CH:46]=2)[C:41]1=[O:69])[C:36]([OH:38])=[O:37]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)o4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ncc(-c5ccccc5)o4)cc3)cc2C1=O
Yield: 72 %

Procedure:
The compound of example 614 was prepared analogous to compound of example 98 by hydrolysis of compound of example 613.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[C@H:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].C([O-])(=O)[C@@H]([C@H](C([O-])=O)O)O.[C:39]1([S:45]([OH:48])(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(O)(C)C.O>[CH3:1][CH2:2][O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:18])[C:10]([C:19]([O:21][CH3:22])=[O:20])=[C:9]([CH3:23])[NH:8][C:7]=1[CH2:24][O:25][CH2:26][CH2:27][NH2:28])=[O:5].[CH:42]1[CH:41]=[CH:40][C:39]([S:45]([OH:48])(=[O:47])=[O:46])=[CH:44][CH:43]=1
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@H]1c1ccccc1Cl
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: O=S(=O)(O)c1ccccc1
Solvent: O
Solvent: CC(C)O
Product: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reaction time: 2 h
Yield: 89.1 %

Procedure:
68.8 gm (0.122 mole, 95.2% de) R (+) amlodipine hemi L(+) tartarate mono DMSO solvate prepared as per example-2 was suspended in aqueous isopropanol (70 ml IPA: 250 ml distilled water) and a solution of benzene sulfonic acid (21.28 gm of 90% technical grade, 0.122 mole) in 1150 ml water was added. The reaction mixture was stirred for 2 hrs and the slurry was filtered, washed with distilled water, hexane, the solid was dried under vac. at 40° C. till constant weight to give R(+) amlodipine besylate (66.74 gm, 89.1% yield) 98.7 ee by chiral HPLC.
Reaction SMILES: [CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:34])[F:33])[CH2:5][CH2:4][CH2:3][CH2:2]1.CO.O[Li].O.Cl>O.O1CCCC1>[CH:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][C:7]=2[C:32]([F:35])([F:33])[F:34])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.2 %

Procedure:
To a solution of ethyl 2-(7-(4-cyclopentyl-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (38.7 mg, 0.080 mmol) in a mixed solvent of methanol (1.5 mL), tetrahydrofuran (0.5 mL), and water (0.5 mL) was added LiOH hydrate (11.7 mg, 0.279 mmol). The mixture was stirred at room temperature overnight before the mixture was acidified to pH 4 with 1 N aqueous HCl solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure and dried under vacuum. The foam was triturated with water to give a solid. The solid was filtered to give the title compound as a light pink solid (25.7 mg). LCMS m/z=458.4 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.56-1.70 (m, 4H), 1.80-1.87 (m, 2H), 1.95-2.11 (m, 3H), 2.34 (dd, J=16.04, 8.97 Hz, 1H), 2.59-2.74 (m, 4H), 3.21-3.25 (m, 1H), 3.41-3.49 (m, 1H), 5.11 (s, 2H), 6.70 (dd, J=8.72, 2.40 Hz, 1H), 6.92 (d, J=2.27 Hz, 1H), 7.19 (d, J=8.72 Hz, 1H), 7.61 (d, J=8.00 Hz, 1H), 7.68 (d, J=8.00 Hz, 1H), 7.70 (s, 1H), 10.45 (s, 1H), 12.18 (bs, 1H).
Reaction SMILES: [C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]1[C:17]([O:19][CH3:20])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CI.[Li+].[CH3:24]C([N-]C(C)C)C>C1COCC1>[C:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1([CH3:24])[C:17]([O:19][CH3:20])=[O:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1c2ccccc2CN1C(=O)OC(C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)c2ccccc2CN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution N-BOC-1,3-dihydro-2H-isoindole-1-carboxylic acid, methyl ester (38 mmol) and MeI (10 mL, 160 mmol) in 150 mL of anhydrous THF at −30° C. was added LDA (Aldrich, 1.5 M in cyclohexane, 51 mL, 76.5 mmol). The reaction was allowed to warm up to rt over 4 hr. The reaction was cooled to −30° C., and was quenched with saturated aqueous solution of NH4Cl (50 mL). The resulting mixture was partitioned between EtOAc and brine, and the product was extracted with EtOAc (3×100 mL). The combined extracts were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted with 10:1 to 5:1 hexane/ether to afford N-BOC-1,3-dihydro-1-methyl-2H-isoindole-1 -carboxylic acid, methyl ester.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:10]=3[N:11]=2)[CH2:3][CH2:2]1.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O.O>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:10]=3[N:11]=2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2oc(N3CCOCC3)nc2c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2oc(N3CCOCC3)nc2c1
Yield: 30.7 %

Procedure:
A solution of 2-morpholino-5-nitrobenzo[d]oxazole (130 mg, 0.52 mmol) in ethanol/water 1:1 v/v (10 mL) was treated with sodium dithionite (182 mg, 1.04 mmol) at room temperature and then refluxed for 16 h. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over anhydrous MgSO4 and evaporated to afford 35 mg (30%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[C:56]([O:60][C:61]([N:63]1[CH2:68][CH2:67][N:66]([CH2:69][CH2:70][NH2:71])[CH2:65][CH2:64]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]>CN(C=O)C.CO>[C:56]([O:60][C:61]([N:63]1[CH2:64][CH2:65][N:66]([CH2:69][CH2:70][NH:71][C:30]([C:26]2[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]3\[C:17](=[O:22])[NH:18][C:19]4[C:15]\3=[CH:14][C:13]([S:10]([CH2:9][C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=3[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=4)[NH:28][C:27]=2[CH3:29])=[O:32])[CH2:67][CH2:68]1)=[O:62])([CH3:59])([CH3:58])[CH3:57]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NCCN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (505 mg, 1 mmol) in DMF (10 mL) was added HOBt (202 mg, 1.3 eq.), EDAC.HCl (288 mg, 1.5 eq.) and TEA (302 mg, 3 eq.). After stirring at rt for 30 mins, to the mixture was added 4-(2-amino-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (298 mg, 1.3 eq.). After stirring at 40° C. for overnight, the reaction was diluted with methanol (2 mL), the precipitate was collected by vacuum filtration, washed with methanol, water and dried to give 700 mg of 4-[2-({5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester as a yellow solid.
Reaction SMILES: [F:1][C:2]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]([OH:8])[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10].C(OC(=O)C)(=O)C.[C:23]1(=[N:27]O)[CH2:26][CH2:25][CH2:24]1>N1C=CC=CC=1.CC(C)=O>[F:1][C:2]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]([O:8][N:27]=[C:23]2[CH2:26][CH2:25][CH2:24]2)[NH:6][C:5](=[O:9])[NH:4][C:3]1=[O:10]
Reactant: ON=C1CCC1
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1O
Solvent: CC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1ON=C1CCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
Ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate (6.60 g., 30 mmoles), acetic anhydride (3.27 g., 32 mmoles), pyridine (10 ml.) and acetone (10 ml.) were mixed and allowed to stand overnight at ordinary temperature (18°-23° C.). To this mixture were added cyclobutanone oxime (3.82 g., 45 mmoles) and pyridine (5 ml.) which was heated at 60° C. for 2 hours. Then, volatiles were removed under reduced pressure and the remaining mass was chromatographed on a column of silica gel with chloroform/acetone=85/15(V/V) to give 4.78 g of ethyl 5-fluoro-6-cyclobutylideneaminooxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate.